Differential diagnosis of demyelinating diseases: what's new?

ABSTRACT Background: Acquired demyelinating disorders lead to overlapping visual, pyramidal, sensory, autonomic, and cerebellar deficits and may lead to severe disability. Early diagnosis and start of treatment are fundamental towards preventing further attacks and halting disability. Objective: In this paper we provide an updated overview of the differential diagnoses of acquired demyelinating disorders. Methods: We performed a critical targeted review of the diagnoses of the most prevalent demyelinating disorders: multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD). Results: We discuss the workup, diagnostic criteria and new biomarkers currently being used for the diagnosis of these disease entities taking into account the particularities of the Brazilian population and healthcare system. Conclusion: A comprehensive analysis of medical history, physical examination, biomedical and imaging data should be performed to obtain differential diagnosis. Diagnostic criteria should be mindfully employed considering ethnic and environmental particularities of each patient.


INTRODUCTION
Acquired demyelinating disorders, such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) compromise the optic nerves, brain and spinal cord and lead to a range of clinical symptoms including visual, pyramidal, sensory, autonomic, and cerebellar deficits. The diseases affect mainly young individuals and may lead to severe disability. In fact, MS is the second leading cause of disability of young adults in developed countries 1 .
Prompt diagnosis and initiation of treatment are essential towards preventing attacks and halting the accumulation of disabilities. The ability to perform accurate differential diagnoses is crucial to the good prognosis of patients, however it can be extremely challenging, as the field is dynamic and expanding, different disease entities clinically overlap and access to specific assays is still limited in certain settings. This paper aims to provide an updated practical approach on how to perform the differential diagnoses of suspected acquired demyelinating syndromes taking into account the particularities of the Brazilian population and healthcare system.

METHODS
We performed a targeted literature review pertaining to the diagnosis of MS, NMOSD and MOGAD. Resulting evidence was jointly critically appraised by a junior and a senior neuroimmunologist.

Epidemiological/demographic update: prevalence of ADS in Brazil
Estimating the prevalence of demyelinating disorders in Brazil is challenging due to the absence of representative country-wide prevalence studies, heterogeneous access to qualified health systems and the ethnically diverse population. Nonetheless, a metanalysis described a national MS prevalence of 8.69/100,000 (95% CI: 6.0-12.6), with an association between the prevalence of MS and latitude of study location (OR=1.09; 95% CI: 1.04-1.14), ethnic composition (OR=1.03; 95% CI: 1.01-1.05) and weather. The authors identified a 9% increase in the prevalence rate of MS for the increase of each degree in latitude and a 3% raise in the prevalence of MS for every degree increase in the proportion of white people 2 .
The prevalence of NMOSD is also heterogeneous and influenced by the population' s ethnical background. Different studies report prevalences in Brazil that range from 0.37 to 4.52/100,000 inhabitants with a north-south gradient decrease in the risk of developing NMOSD 3,4 . Prevalence and disease phenotypes are influenced by ethnicity, and worse clinical outcomes are associated with Asian, African and Latin American ancestry 5 .
MOGAD incidence rates worldwide range from 0.16 to 1.4 per 100,000 6 . The proportion of MOG-IgG related acquired demyelinating syndromes (ADS) decreases with age. Higher disease incidences have been reported in pediatric cohorts (39%), than among mixed cohorts of children and adults (29%) or adults (23%) 6 . Ethnicity initially seemed to not be as important with 78-90% (MOGAD) versus 60-63% (NMOSD) of Caucasians, however Brazilian data suggests that it may play a role in the prevalence of the disease 7,8 . The nationwide estimations of the prevalence of MOGAD have not yet been published.

Diagnosis of demyelinating disorders
Demyelinating disorders lead to overlapping clinical syndromes. A methodical diagnostic approach, including thorough investigation of the medical history, neurological examination and complementary tests is helpful towards performing differential diagnoses (Table 1). Unfortunately, not all tests are available in the Brazilian public health system, therefore mindful investigation is suggested to prevent unnecessary financial expenses.
The diagnoses can be obtained through the interpretation of the medical history, neurological examination, biomedical/ imaging tests and application of current diagnostic criteria 9,10 (Tables 2, 3 and 4).  To this day, the diagnosis of MOGAD still relies on the identification of the MOG-IgG antibody in serum. Live cell-based assays are the established gold standard for the identification of the antibody, due to its superior sensitivity and specificity 11 . Unlike what is observed in MS and NMOSD, a portion of patients with MOGAD present with monophasic disease and therefore, might have a MOG IgG serostatus switch over time regardless of immunosuppressive treatment. The final diagnosis of MOGAD should account for the medical history and clinical phenotype of the patient in addition to their serostatus, as a percentage of patients with MS may present with low titers of MOG-IgG, while employed assays may not be adequately sensitive to detect low antibody titers and clear diagnostic criteria for the disease have not yet been defined.

Differential diagnosis
The careful interpretation of medical history, physical examination and additional investigation allows the distinction between the various acquired demyelinating syndromes (Table 5). It is important to highlight that the criteria currently used for the diagnosis of MS and NMOSD were developed and validated in populations with ethnic and environmental backgrounds distinct from what is observed in the Brazilian population, which might compromise the sensitivity and specificity of the criteria. Brazilian neurologists ought to be mindful to identify "red-flags" for atypical demyelinating syndromes and systematically rule out differential diagnoses, including endemic infectious diseases such as HLTV I/II and schistosomiasis.

Role of novel biomarkers
Optical coherence tomography (OCT) is an imaging technique which uses infrared light in a similar manner to that of the ultrasound to measure different biological tissue's backscatter, getting micrometer-resolution images. When used in the retina, it allows the reconstruction of tomographic maps and quantification of axons of the retinal nerve fiber layer (RNFL) and neurons of the macular ganglion cell layer (mGCL) 12 . OCT has consistently been used to screen for subclinical optical abnormalities in patients with demyelinating disorders, however data shows associations between reduced RNFL/mGCL and neurodegeneration with correlations to types of MS, disability and cognitive impairment [12][13][14][15] . In addition, distinct OCT patterns can be used as diagnostic biomarkers aiding in the differential diagnosis of MOGAD from other demyelinating disorders 16,17 .
Neurofilaments (Nf) are structural proteins involved in the radial growth and stability of neurons. Studies have demonstrated that Nf-l has a value as a scientifically useful biomarker of disease activity and therapy effectiveness of groups  Primary progressive multiple sclerosis can be diagnosed in patients with: 1 year of disability progression (retrospectively or prospectively determined) independent of clinical relapse Plus two of the following criteria: One or more T2-hyperintense lesions characteristic of multiple sclerosis in one or more of the following brain regions: periventricular, cortical or juxtacortical, or infratentorial Two or more T2-hyperintense lesions in the spinal cord Presence of CSF-specific oligoclonal bands of patients with inflammatory diseases of the CNS, such as multiple sclerosis and clinically isolated syndrome [18][19][20][21][22] . It is currently not commonly used in clinical practice, as its measure is modulated by body-mass index (BMI), age, and comorbidities which compromise the definition of fixed cutoffs and individually pathological levels of Nf-l 23 . Recent data has shown that Nf-l levels can be clinically employed to predict disease activity and disease-modifying therapy effectiveness in the real world setting on an individual level if percentiles and Nf-l Z scores are used 23 . Nonetheless, the description is new and the practice still not widespread. Glial fibrillary acidic protein (GFAP) is a principal intermediate filament that forms the astrocyte cytoskeleton and is regarded as a biomarker of astrocyte injury 24 . Evidence describes its role as a potential diagnostic and prognostic biomarker in NMOSD, a known astrocytopathy, however its use is still currently limited to scientific purposes 25,26 .

DISCUSSION
Acquired demyelinating disorders lead to a plethora of clinical syndromes which are common among distinct nosologies.
In the past 20 years, anti-aquaporin 4 antibodies (AQP4-IgG), anti-MOG antibodies (MOG-IgG) and their associated disease entities, AQP-4 IgG NMOSD and MOGAD, were described. Since then, making a differential diagnosis between the most prevalent acquired demyelinating disorders has become more challenging, especially in places where environmental and genetic conditions are distinct to those of the settings where studies guiding diagnostic criteria were carried out.
A methodical approach to the diagnostic process can aid in achieving timely accurate diagnoses. In addition to a thorough medical history and neurological examination, biomedical and imaging data can provide crucial information to aid in identifying each disease. Although clinical phenotypes often overlap, integrated analysis of demographic, clinical, biomedical, and imaging data is particular to each disease and therefore should be interpreted together.
As the field further develops, new technologies and biomarkers are systematically being studied and translated from the bench to the bedside. For now, it is suggested that neurologists examine the validity, specificity, and sensitivity for individual use of each new diagnostic tool before applying it in their routine diagnostic practice. In conclusion, a comprehensive analysis of the diagnostic workup should be performed to obtain a differential diagnosis of an acquired demyelinating disorder. Diagnostic criteria should be mindfully employed considering ethnic and environmental particularities of each patient.